Brain damage in stroke and in cardiac arrest results from an inadequate supply of blood to the brain, termed brain ischemia. Brain ischemia depletes the energy stores of affected brain regions and causes the excessive release of glutamate and other neurotransmitters from metabolically compromised nerve terminals. Our goal is to discover synthetic, selective antagonists of the ion channels controlling the release of glutamate and other neurotransmitters. Such compounds may be employed as drugs to limit brain damage in focal ischemia (stroke) and global ischemia (resulting from cardiac arrest or complications of cardiac surgery). Using novel drug discovery methology based on a proprietary method for monitoring neurotransmitter release from brain nerve terminals, we have developed a novel compound series of synthetic glutamate release blockers, members of which are highly neuroprotective in an animal model of brain ischemia. During Phase II, we hope to incorporate rational drug design strategies resulting from knowledge on the structure of the site of interaction of these neuroprotective compounds with its ion channel targets. Candidates for drug development are likely to emerge from the Phase II project period, and selection of such candidates is the central goal of the project.